PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) constitutes a substantial societal and personal burden. Clinical trial failures indicate the need for a better mechanistic understanding of this complex disease. Triglycerides, which are measured in routine clinical check-ups, are a source of fatty acids (FAs). Our previous work has shown a significant association between polyunsaturated triglycerides (PUTGs) and AD. Interestingly, these PUTGs were found to carry omega-3 polyunsaturated fatty acids (n-3 FAs), which have shown to improve cognitive function in aging populations. Many clinical trials have investigated n-3 FA supplementation in AD patients, but have resulted in disappointment. The literature does suggest a genetic influence on patient response to n-3 FA supplementation. APOE ?4 is a genetic risk factor for late-onset AD. In AD patients, APOE ?4 noncarriers experience improved cognitive function, while APOE ?4 carriers do not experience the same benefit. Our goal is to investigate the association of PUTGs and n-3 FAs with cross-sectional and longitudinal changes in AD biomarkers, and the genomic contribution of PUTGs and n-3 FAs to pathologic AD mechanisms. To achieve this goal, we will use a hypothesis-driven, integrative approach that will incorporate multi-omics (genomics, metabolomics, transcriptomics) and multi-modal biomarker (blood, CSF, neuroimaging) data. We will use data from ADNI, WRAP, and AMP-AD cohorts. First, we show preliminary results for an association between baseline n-3 FAs and ?A/T/N/V? (amyloid, tau, neurodegeneration, and microvascular disease burden) biomarkers at baseline. We will test if PUTGs and n-3 FAs at baseline predict longitudinal changes in A/T/N/V biomarkers up to 8 years and conversion of mild cognitive impairment (MCI) to AD after 36 months from baseline. ?A/T/N/V? is based on the recently proposed NIA-Alzheimer?s Association 2018 Research Framework using CSF and neuroimaging biomarkers (brain atrophy and white matter hyperintensity volume (MRI) and brain glucose metabolism (FDG-PET)). Second, we will investigate genetic mechanisms that may contribute to AD pathophysiology by focusing specifically on PUTG and n-3 FA pathway-related genes. Using publicly available databases, we have manually curated a candidate gene list that is related to PUTG and n-3 FA pathways and found associations between serum PUTG levels and gene candidates. We will determine if genetic variation in PUTG and n-3 FA related-pathways associate with serum n-3 FAs and A/T/N/V biomarkers at baseline and predict longitudinal changes in A/T/N/V biomarkers. Finally, we will determine if these gene candidates are differentially expressed in AD and if genetic variations have significant effects on gene expression levels in blood and brain. Our study has strong potential to provide insight into how serum levels of PUTGs and n-3 FAs are associated with AD and to yield novel diagnostic and therapeutic targets based on genetic-validated mechanisms.